Magnetic resonance imaging (MRI) has become a useful tool for diagnosis and for research. The current technology relies on detecting the energy emitted when the hydrogen nuclei in the water contained in tissues and body fluids returns to a ground state subsequent to excitation with a radio frequency. Observation of this phenomenon depends on imposing a magnetic field across the area to be observed, so that the distribution of hydrogen nuclear spins is statistically oriented in alignment with the magnetic field, and then imposing an appropriate radio frequency. This results in an excited state in which this statistical alignment is disrupted. The decay of the distribution to the ground state can then be measured as an emission of energy, the pattern of which can be detected as an image.
While the above described process is theoretically possible, it turns out that the relaxation rate of the relevant hydrogen nuclei, left to their own devices, is too slow to generate detectable amounts of energy, as a practical matter. In order to remedy this, the area to be imaged is supplied with a contrast agent, generally a strongly paramagnetic metal, which effectively acts as a catalyst to accelerate the decay, thus permitting sufficient energy to be emitted to create a detectable bright signal. To put it succinctly, contrast agents decrease the relaxation time and increase the reciprocal of the relaxation time—i.e., the “relaxivity” of the surrounding hydrogen nuclei.
Two types of relaxation times can be measured. T1 is the time for the magnetic distribution to return to 63% of its original distribution longitudinally with respect to the magnetic field and the relaxivity ρ1, is its reciprocal. T2 measures the time wherein 63% of the distribution returns to the ground state transverse to the magnetic field. Its reciprocal is the relaxivity index ρ2. In general, the relaxation times and relaxivities will vary with the strength of the magnetic field; this is most pronounced in the case of the longitudinal component.
Thus, a desirable characteristic of any contrast agents is to provide the signal with an enhanced relaxivity both for ρ1 and ρ2. The present invention provides such contrast agents.
It is also advantageous to facilitate the excretion of the paramagnetic ion, which may otherwise be toxic if it is retained in a subject. Thus, it would be advantageous to provide a mechanism for cleaving the chelated metal ion from the particles or from any lipid components that might result in cellular or liver uptake.
There is an extensive literature regarding contrast agents which are based on chelated paramagnetic metals. For example, U.S. Pat. Nos. 5,512,294 and 6,132,764 describe liposomal particles with metal chelates on their surfaces as MRI contrast agents. U.S. Pat. Nos. 5,064,636 and 5,120,527 describe paramagnetic oil emulsions for MRI in the gastrointestinal tract. U.S. Pat. Nos. 5,614,170 and 5,571,498 describe emulsions that incorporate lipophilic gadolinium chelates, e.g., gadolinium diethylene-triamine-pentaacetic acid-bis-oleate (Gd-DTPA-BOA) as blood pool contrast agents.
U.S. Pat. No. 5,804,164 describes water-soluble, lipophilic agents which comprise particularly designed chelating agents and paramagnetic metals. U.S. Pat. No. 6,010,682 and other members of the same patent family describe lipid soluble chelating contrast agents containing paramagnetic metals which are said to be able to be administered in the form of liposomes, micelles or lipid emulsions.
Thus, in general, contrast agents may take the form of paramagnetic metals such as rare earth metals or iron mobilized in a form that permits substantial concentrations of the paramagnetic metal to be delivered to the desired imaging area.
One method for providing useful concentrations of contrast agents has been described by the present applicants in U.S. Pat. Nos. 5,780,010 and 5,909,520. A nanoparticle is formed from an inert core surrounded by a lipid/surfactant coating. The lipid/surfactant coating can then be modified to couple the particle to a chelating agent containing a paramagnetic metal. In addition, the particle can be coupled to a ligand for targeting to a specific site.
The present invention provides an improvement in the design of contrast agents whereby the relaxivity of the signal can be enhanced dramatically, and excretion can be facilitated.